Figure 2: The pathogenic roles of H2S at different stages of diabetes development.

Elevated endogenous hydrogen sulfide (H2S) levels in pancreatic β-cells and hepatocytes have crucial roles in the onset of diabetes. At late stages of the disease, endogenous H2S levels are lower in the affected organs and tissues, such…

Hydrogen sulfide (H2S) is thought to act through several pathways, some of which are illustrated above, to reduce inflammation and protect tissues from injury (such as ulceration in the gastrointestinal tract). H2S can suppress leukocyt…

Who knew that rotten eggs could be so useful medically? Scientists have identified a certain compound that is produced when eggs go bad. It’s called hydrogen sulfide, and has been proven to be effective in reversing mitochondrial damage and treating diseases like stroke and dementia.

The study, out of the University of Exeter, found that a new compound known as AP39, could target certain parts of the cell such as the mitochondria, which is known as the “powerhouse” of the cell, when inserted into the body. Mitochondria manage cell growth, cycle, and death, and are also a source of chemical energy. Because it plays a role in a lot of diseases, such as cardiovascular disease, scientists believe that preventing mitochondrial damage could have a therapeutic effect on certain conditions like stroke, heart failure, arthritis, diabetes, dementia, and even aging.

AP39 is able to deliver very small amounts of hydrogen sulfide — which is found both in rotten eggs and human farts — to cells to begin its work. “Although hydrogen sulfide is well known as a pungent, foul-smelling gas in rotten eggs and flatulence, it is naturally produced in the body and could in fact be a healthcare hero with significant implications for future therapies for a variety of diseases,” study author Dr. Mark Wood said in a press release. It’s important to note, however, that hydrogen sulfide in large doses can be deadly.

Scientists have studied the effects of hydrogen sulfide in the past, previously noting that it could play a role in fighting aging. One study, published in 2013, found that the chemical had significant effects on the cardiovascular and nervous systems in the body. Scientists noted that hydrogen sulfide “may become the next potent agent for preventing and ameliorating the symptoms of aging and age-associated diseases.”

With the newest study, in which researchers are targeting mitochondria through AP39, the chemical has been shown to induce survival in 80 percent of mitochondria that are under destructive conditions. “When cells become stressed by disease, they draw in enzymes to generate minute quantities of hydrogen sulfide,” said Professor Matt Whiteman of the University of Exeter Medical School, in the release. “This keeps the mitochondria ticking over and allows cells to live. If this doesn’t happen, the cells die and lose the ability to regulate survival and control inflammation. We have exploited this natural process by making a compound, called AP39, which slowly delivers very small amounts of this gas specifically to the mitochondria. Our results indicate that if stressed cells are treated with AP39, mitochondria are protected and cells stay alive.” The researchers hope to move their experiments forward to be tested in humans next.

Hydrogen sulfide: Function in the body

Hydrogen sulfide is produced in small amounts by some cells of the mammalian body and has a number of biological signaling functions. (Only two other such gases are currently known: nitric oxide (NO) and carbon monoxide (CO).)

Though both nitric oxide (NO) and hydrogen sulfide have been shown to relax blood vessels, their mechanisms of action are different: while NO activates the enzyme guanylyl cyclase, H
2S activates ATP-sensitive potassium channels in smooth muscle cells. Researchers are not clear how the vessel-relaxing responsibilities are shared between nitric oxide and hydrogen sulfide. However, there exists some evidence to suggest that nitric oxide does most of the vessel-relaxing work in large vessels and hydrogen sulfide is responsible for similar action in smaller blood vessels.[49]

Recent findings suggest strong cellular crosstalk of NO and H
2S,[50] demonstrating that the vasodilatatory effects of these two gases are mutually dependent. Additionally, H
2S reacts with intracellular S-nitrosothiols to form the smallest S-nitrosothiol (HSNO), and a role of hydrogen sulfide in controlling the intracellular S-nitrosothiol pool has been suggested.[51]

Like nitric oxide, hydrogen sulfide is involved in the relaxation of smooth muscle that causes erection of the penis, presenting possible new therapy opportunities for erectile dysfunction.[52][53]

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INVOLVEMENT IN DISEASES

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Hydrogen sulfide deficiency after heart attack

A hydrogen sulfide (H2S) deficiency can be detrimental to the vascular function after an acute myocardial infarction (AMI).[54]AMIs can lead to cardiac dysfunction through two distinct changes; increased oxidative stress via free radical accumulation and decreased NO bioavailability.[55] Free radical accumulation occurs due to increased electron transport uncoupling at the active site of endothelial nitric oxide synthase (eNOS), an enzyme involved in converting L-arginine to NO.[54][55] During an AMI, oxidative degradation of tetrahydrobiopterin (BH4), a cofactor in NO production, limits BH4 availability and limits NO productionby eNOS.[55] Instead, eNOS reacts with oxygen, another cosubstrates involved in NO production. The products of eNOS are reduced to superoxides, increasing free radical production and oxidative stress within the cells.[54] A H2S deficiency impairs eNOS activity by limiting Akt activation and inhibiting Akt phosphorylation of the eNOSS1177 activation site.[54][56] Instead, Akt activity is increased to phosphorylate the eNOST495 inhibition site, downregulating eNOS production of NO.[54][56]

H2S therapy uses a H2S donor, such as diallyl trisulfide (DATS), to increase the supply of H2S to an AMI patient. H2S donors reduce myocardial injury and reperfusion complications.[54] Increased H2S levels within the body will react with oxygen to produce sulfane sulfur, a storage intermediate for H2S.[54] H2S pools in the body attracts oxygen to react with excess H2S and eNOS to increase NO production.[54] With increased use of oxygen to produce more NO, less oxygen is available to react with eNOS to produce superoxides during an AMI, ultimately lowering the accumulation of reactive oxygen species (ROS).[54] Furthermore, decreased accumulation of ROS lowers oxidative stress in vascular smooth muscle cells, decreasing oxidative degeneration of BH4.[55] Increased BH4 cofactor contributes to increased production of NO within the body.[55]Higher concentrations of H2S directly increase eNOS activity through Akt activation to increase phosphorylation of the eNOSS1177 activation site, and decrease phosphorylation of the eNOST495 inhibition site.[54][56] This phosphorylation process upregulates eNOS activity, catalyzing more conversion of L-arginine to NO.[54][56] Increased NO production enables soluble guanylyl cyclase (sGC) activity, leading to an increased conversion of guanosine triphosphate (GTP) to 3’,5’-cyclic guanosine monophosphate (cGMP).[57] In H2S therapy immediately following an AMI, increased cGMP triggers an increase in protein kinase G (PKG) activity.[58] PKG reduces intracellular Ca2+ in vascular smooth muscle to increase smooth muscle relaxation and promote blood flow.[58] PKG also limits smooth muscle cell proliferation, reducing intima thickening following AMI injury, ultimately decreasing myocardial infarct size.[54][57]

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Hydrogen sulfide in other diseases

In Alzheimer's disease the brain's hydrogen sulfide concentration is severely decreased.[59] In a certain rat model ofParkinson's disease, the brain's hydrogen sulfide concentration was found to be reduced, and administering hydrogen sulfide alleviated the condition.[60] In trisomy 21 (Down syndrome) the body produces an excess of hydrogen sulfide.[47]Hydrogen sulfide is also involved in the disease process of type 1 diabetes. The beta cells of the pancreas in type 1 diabetes produce an excess of the gas, leading to the death of these cells and to a reduced production of insulin by those that remain.[49]